Planarian worms have amazed scientists with their apparently limitless ability to regenerate. Researchers have been studying their ability to replace aged or damaged tissues and cells in a bid to understand the mechanisms underlying their longevity.

Dr Aziz Aboobaker from the University’s School of Biology, said: “We’ve been studying two types of planarian worms; those that reproduce sexually, like us, and those that reproduce asexually, simply dividing in two. Both appear to regenerate indefinitely by growing new muscles, skin, guts and even entire brains over and over again. “Usually when stem cells divide — to heal wounds, or during reproduction or for growth — they start to show signs of ageing. This means that the stem cells are no longer able to divide and so become less able to replace exhausted specialised cells in the tissues of our bodies. Our ageing skin is perhaps the most visible example of this effect. Planarian worms and their stem cells are somehow able to avoid the ageing process and to keep their cells dividing.” One of the events associated with ageing cells is related to telomere length. In order to grow and function normally, cells in our bodies must keep dividing to replace cells that are worn out or damaged. During this division process, copies of the genetic material must pass on to the next generation of cells. The genetic information inside cells is arranged in twisted strands of DNA called chromosomes. At the end of these strands is a protective ‘cap’ called a telomere. Telomeres have been likened to the protective end of a shoelace which stops strands from fraying or sticking to other strands.

Theoretical immortality

Each time a cell divides the protective telomere ‘cap’ gets shorter. When they get too short, the cell loses its ability to renew and divide. In an immortal animal we would therefore expect cells to be able to maintain telomere length indefinitely so that they can continue to replicate. Dr Aboobaker predicted that planarian worms actively maintain the ends of their chromosomes in adult stem cells, leading to theoretical immortality.

Dr Thomas Tan made some exciting discoveries for this paper as part of his PhD. He performed a series of challenging experiments to explain the worm’s immortality. In collaboration with the rest of the team, he also went some way to understanding the clever molecular trick that enabled cells to go on dividing indefinitely without suffering from shortened chromosome ends.

Previous work, leading to the award of the 2009 Nobel Prize for Physiology or Medicine, had shown that telomeres could be maintained by the activity of an enzyme called telomerase. In most sexually reproducing organisms the enzyme is most active only during early development. So as we age, telomeres start to reduce in length.

This project identified a possible planarian version of the gene coding for this enzyme and turned down its activity. This resulted in reduced telomere length and proved it was the right gene. They were then able to confidently measure its activity and resulting telomere length and found that asexual worms dramatically increase the activity of this gene when they regenerate, allowing stem cells to maintain their telomeres as they divide to replace missing tissues.

Clearer proof

Dr Tan pointed out the importance of the interdisciplinary expertise: “It was serendipitous to be sandwiched between Professor Edward Louis’s yeast genetics lab and the Children’s Brain Tumour Research Centre, both University of Nottingham research centres with expertise in telomere biology. Aziz and Ed kept demanding clearer proof and I feel we have been able to give a very satisfying answer.”

However, what puzzled the team is that sexually reproducing planarian worms do not appear to maintain telomere length in the same way. The difference they observed between asexual and sexual animals was surprising, given that they both appear to have an indefinite regenerative capacity. The team believe that sexually reproductive worms will eventually show effects of telomere shortening, or that they are able to use another mechanism to maintain telomeres that would not involve the telomerase enzyme.

Dr Aboobaker concluded: “Asexual planarian worms demonstrate the potential to maintain telomere length during regeneration. Our data satisfy one of the predictions about what it would take for an animal to be potentially immortal and that it is possible for this scenario to evolve. The next goals for us are to understand the mechanisms in more detail and to understand more about how you evolve an immortal animal.”

Professor Douglas Kell, BBSRC Chief Executive, said: “This exciting research contributes significantly to our fundamental understanding of some of the processes involved in ageing, and builds strong foundations for improving health and potentially longevity in other organisms, including humans.”

Compártelo:

For the last decade cancer research has been guided by a common vision of how a single cell, outcompeting its neighbors, evolves into a malignant tumor.

Through a series of random mutations, genes that encourage cellular division are pushed into overdrive, while genes that normally send growth-restraining signals are taken offline.

With the accelerator floored and the brake lines cut, the cell and its progeny are free to rapidly multiply. More mutations accumulate, allowing the cancer cells to elude other safeguards and to invade neighboring tissue and metastasize.

These basic principles — laid out 11 years ago in a landmark paper, “The Hallmarks of Cancer,” by Douglas Hanahan and Robert A. Weinberg, and revisited in a follow-up article this year — still serve as the reigning paradigm, a kind of Big Bang theory for the field.

But recent discoveries have been complicating the picture with tangles of new detail. Cancer appears to be even more willful and calculating than previously imagined.

Most DNA, for example, was long considered junk — a netherworld of detritus that had no important role in cancer or anything else. Only about 2 percent of the human genome carries the code for making enzymes and other proteins, the cogs and scaffolding of the machinery that a cancer cell turns to its own devices.

These days “junk” DNA is referred to more respectfully as “noncoding” DNA, and researchers are finding clues that “pseudogenes” lurking within this dark region may play a role in cancer.

“We’ve been obsessively focusing our attention on 2 percent of the genome,” said Dr. Pier Paolo Pandolfi, a professor of medicine and pathology at Harvard Medical School. This spring, at the annual meeting of the American Association for Cancer Research in Orlando, Fla., he described a new “biological dimension” in which signals coming from both regions of the genome participate in the delicate balance between normal cellular behavior and malignancy.

As they look beyond the genome, cancer researchers are also awakening to the fact that some 90 percent of the protein-encoding cells in our body are microbes. We evolved with them in a symbiotic relationship, which raises the question of just who is occupying whom.

“We are massively outnumbered,” said Jeremy K. Nicholson, chairman of biological chemistry and head of the department of surgery and cancer at Imperial College London. Altogether, he said, 99 percent of the functional genes in the body are microbial.

In Orlando, he and other researchers described how genes in this microbiome — exchanging messages with genes inside human cells — may be involved with cancers of the colon, stomach, esophagus and other organs.

These shifts in perspective, occurring throughout cellular biology, can seem as dizzying as what happened in cosmology with the discovery that dark matter and dark energy make up most of the universe: Background suddenly becomes foreground and issues once thought settled are up in the air. In cosmology the Big Bang theory emerged from the confusion in a stronger but more convoluted form. The same may be happening with the science of cancer.

Exotic Players

According to the central dogma of molecular biology, information encoded in the DNA of the genome is copied by messenger RNA and then carried to subcellular structures called ribosomes, where the instructions are used to assemble proteins. Lurking behind the scenes, snippets called microRNAs once seemed like little more than molecular noise. But they have been appearing with increasing prominence in theories about cancer.

By binding to a gene’s messenger RNA, microRNA can prevent the instructions from reaching their target — essentially silencing the gene — and may also modulate the signal in other ways. One presentation after another at the Orlando meeting explored how microRNAs are involved in the fine-tuning that distinguishes a healthy cell from a malignant one.

Ratcheting the complexity a notch higher, Dr. Pandolfi, the Harvard Medical School researcher, laid out an elaborate theory involving microRNAs and pseudogenes. For every pseudogene there is a regular, protein-encoding gene. (Both are believed to be derived from a common ancestral gene, the pseudogene shunted aside in the evolutionary past when it became dysfunctional.) While normal genes express their will by sending signals of messenger RNA, the damaged pseudogenes either are mute or speak in gibberish.

Or so it was generally believed. Little is wasted by evolution, and Dr. Pandolfi hypothesizes that RNA signals from both genes and pseudogenes interact through a language involving microRNAs. (These signals are called ceRNAs, pronounced “sernas,” meaning “competing endogenous RNAs.”)

His lab at Beth Israel Deaconess Medical Center in Boston is studying how this arcane back channel is used by genes called PTEN and KRAS, commonly implicated in cancer, to confer with their pseudotwins. The hypothesis is laid out in more detail this monthin an essay in the journal Cell.

Fueled by the free espresso offered by pharmaceutical companies hawking their wares, scientists at the Orlando meeting moved from session to session and browsed corridors of posters, looking for what might have recently been discovered about other exotic players: lincRNA, (for large intervening noncoding), siRNA (small interfering), snoRNA (small nucleolar) and piRNA (Piwi-interacting (short for “P-element induced wimpy testis” (a peculiar term that threatens to pull this sentence into a regress of nested parenthetical explanations))).

In their original “hallmarks” paper — the most cited in the history of Cell — Dr. Hanahan and Dr. Weinberg gathered a bonanza of emerging research and synthesized it into six characteristics. All of them, they proposed, are shared by most and maybe all human cancers. They went on to predict that in 20 years the circuitry of a cancer cell would be mapped and understood as thoroughly as the transistors on a computer chip, making cancer biology more like chemistry or physics — sciences governed by precise, predictable rules.

Now there appear to be transistors inside the transistors. “I still think that the wiring diagram, or at least its outlines, may be laid out within a decade,” Dr. Weinberg said in an e-mail. “MicroRNAs may be more like minitransistors or amplifiers, but however one depicts them, they still must be soldered into the circuit in one way or another.”

In their follow-up paper, “Hallmarks of Cancer: The Next Generation,” he and Dr. Hanahan cited two “emerging hallmarks” that future research may show to be crucial to malignancy — the ability of an aberrant cell to reprogram its metabolism to feed its wildfire growth and to evade destruction by the immune system.

Unwitting Allies

Even if all the lines and boxes for the schematic of the cancer cell can be sketched in, huge complications will remain. Research is increasingly focused on the fact that a tumor is not a homogeneous mass of cancer cells. It also contains healthy cells that have been conscripted into the cause.

Cells called fibroblasts collaborate by secreting proteins the tumor needs to build its supportive scaffolding and expand into surrounding tissues. Immune system cells, maneuvered into behaving as if they were healing a wound, emit growth factors that embolden the tumor and stimulate angiogenesis, the generation of new blood vessels. Endothelial cells, which form the lining of the circulatory system, are also enlisted in the construction of the tumor’s own blood supply.

All these processes are so tightly intertwined that it is difficult to tell where one leaves off and another begins. With so much internal machinery, malignant tumors are now being compared to renegade organs sprouting inside the body.

As the various cells are colluding, they may also be trading information with cells in another realm — the micro-organisms in the mouth, skin, respiratory system, urogenital tract, stomach and digestive system. Each microbe has its own set of genes, which can interact with those in the human body by exchanging molecular signals.

“The signaling these microbes do is dramatically complex,” Dr. Nicholson said in an interview at Imperial College. “They send metabolic signals to each other — and they are sending chemicals out constantly that are stimulating our biological processes.

“It’s astonishing, really. There they are, sitting around and doing stuff, and most of it we don’t really know or understand.”

People in different geographical locales can harbor different microbial ecosystems. Last year scientists reported evidence that the Japanese microbiome has acquired a gene for a seaweed-digesting enzyme from a marine bacterium. The gene, not found in the guts of North Americans, may aid in the digestion of sushi wrappers. The idea that people in different regions of the world have co-evolved with different microbial ecosystems may be a factor — along with diet, lifestyle and other environmental agents — in explaining why they are often subject to different cancers.

The composition of the microbiome changes not only geographically but also over time. With improved hygiene, dietary changes and the rising use of antibiotics, levels of the microbe Helicobacter pylori in the human gut have been decreasing in developing countries, and so has stomach cancer. At the same time, however, esophageal cancer has been increasing, leading to speculation that H. pylori provides some kind of protective effect.

At the Orlando meeting, Dr. Zhiheng Pei of New York University suggested that the situation is more complex. Two different types of microbial ecosystems have been identified in the human esophagus. Dr. Pei’s lab has found that people with an inflamed esophagus or with a precancerous condition called Barrett’s esophagus are more likely to harbor what he called the Type II microbiome.

“At present, it is unclear whether the Type II microbiome causes esophageal diseases or gastro-esophageal reflux changes the microbiome from Type I to II,” Dr. Pei wrote in an e-mail. “Either way, chronic exposure of the esophagus to an abnormal microbiome could be an essential step in esophageal damage and, ultimately, cancer.”

Unseen Enemies

At a session in Orlando on the future of cancer research, Dr. Harold Varmus, the director of the National Cancer Institute, described the Provocative Questions initiative, a new effort to seek out mysteries and paradoxes that may be vulnerable to solution.

“In our rush to do the things that are really obvious to do, we’re forgetting to pay attention to many unexplained phenomena,” he said.

Why, for example, does the Epstein-Barr virus cause different cancers in different populations? Why do patients with certain neurological diseases like Parkinson’s, Huntington’s, Alzheimer’s and Fragile X seem to be at a lower risk for most cancers? Why are some tissues more prone than others to developing tumors? Why do some mutations evoke cancerous effects in one type of cell but not in others?

With so many phenomena in search of a biological explanation, “Hallmarks of Cancer: The Next Generation” may conceivably be followed by a second sequel — with twists as unexpected as those in the old “Star Trek” shows. The enemy inside us is every bit as formidable as imagined invaders from beyond. Learning to outwit it is leading science deep into the universe of the living cell.